Action Points

Catch-up human papillomavirus (HPV) vaccination was associated with a reduced risk of cervical pre-cancer for younger women who started it at earlier ages, but not women ages ≥21.

Note that additional research is needed to confirm the limited effectiveness of catch-up vaccination for women aged 21-26 years.

Catch-up human papillomavirus (HPV) vaccination was associated with a reduced risk of cervical pre-cancer for younger women who started it at earlier ages, but not women ages ≥21, researchers found.

A significantly reduced risk for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was found for women who received at least three doses of HPV vaccine, and their first dose at ages 14-17 (adjusted RR 0.52, 95% CI 0.36-0.74), reported Michael J. Silverberg, PhD, of Kaiser Permanente in Oakland, California, and colleagues.

However, there was no significant protection if the woman received at least three doses HPV vaccine, and their first dose at ages ≥21 (adjusted RR 0.95, 95% CI 0.78-1.17), the authors wrote in Lancet Child & Adolescent Health.

"The evidence suggests that protection is strongest the earlier the vaccine is initiated, and after the age of 21, the evidence of effectiveness is unclear. Further research in other settings, and using the recently introduced nonavalent vaccine, will now be needed to assess the effectiveness of vaccinating women ages 21-26 years," Silverberg said in a statement.

He added that their research found that even girls who did not receive the full vaccine series at ages 11-12 can "still benefit from significant protection if they receive the three full doses of the vaccine by age 20."

The authors added that evidence in support of a vaccine effect on "high-grade pre-cancerous lesions," including cervical intraepithelial neoplasia (CIN) grades 2, 2/3, 3, adenocarcinoma in situ or cancer (CIN2+ or CIN3+), is "limited and consists mainly of study findings showing ecological decreases in CIN2+ incidence over time."

They performed a nested case-control study of women at Kaiser Permanente Northern California of women with CIN2+ or CIN3+ confirmed by histology. Each case was matched to five randomly selected controls, which were age-matched women without CIN2+ or CIN3+. All cases and controls were ages ≤26 when the HPV quadrivalent vaccine became available in 2006, the authors said.

Overall, there were 4,357 CIN2+ cases and 21,773 matched controls, which also included a subset of 1,849 CIN3+ cases with 9,242 matched controls. Compared with controls, cases were more likely to be non-Hispanic white, and more likely to have a history of smoking, recent hormonal contraceptive use, and recent sexually transmitted infections, the authors said. Of the cases, 40% were CIN3, 38% were CIN 2/3 and 20% were CIN2, while <1% were cancer.

Only 10% of cases and 11% of controls had any prior HPV vaccination, which did confer protection against CIN2+ (adjusted RR 0.82, 95% CI 0.73-0.93). The authors also found women who received at least three doses of HPV vaccine, with the first dose at ages 18-20, also had a significantly reduced risk of CIN2+ (adjusted RR 0.65, 95% CI 0.49-0.88).

The authors described "even more robust associations" when examining the subset of CIN3+ cases. Women who received at least one dose of HPV vaccine were at a reduced risk for CIN3+ (adjusted RR 0.77, 95% CI 0.64-0.94) and a similar reduced risk of CIN3+ among women who received at least three doses of vaccine at ages 14-17 (adjusted RR 0.27, 95% CI 0.13-0.56) and ages 18-20 (adjusted RR 0.59, 95% CI 0.36-0.97).

An accompanying editorial by Sarah Dilley, MD and Warner Huh, MD, of the University of Alabama at Birmingham, described this as "compelling data" to support catch-up HPV vaccination in older adolescents, noting an "impressive reduction" in CIN3+ among girls who were ages 14-17 at first dose of the vaccine (adjusted RR 0.44, 95% CI 0.26-0.74).

"These data support the updated [CDC Advisory Committee on Immunization Practices] HPV vaccination schedule, which recommends administration of three doses to any women who start the vaccine series after age 14 years," the editorialists wrote. "However ...prospective efficacy studies have shown benefits for catch-up vaccination up to at least age 26 years, [so] more data is needed before abandoning this practice."

Study limitations included potential misclassification of clinically ascertained study measurements, such as smoking, as well as residual confounding "related to screening vigilance."

The study was funded by the NCI.

Silverberg and co-authors disclosed no relevant relationships with industry.

Dilley disclosed support from Merck. Huh disclosed support from Merck, Antiva, and Pathovax.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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